Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action

BACKGROUND AND PURPOSE

Two non-psychoactive cannabinoids, cannabidiol (CBD) and cannabichromene (CBC), are known
to modulate in vitro the activity of proteins involved in nociceptive mechanisms,
including transient receptor potential (TRP) channels of vanilloid type-1 (TRPV1) and of
ankyrin type-1 (TRPA1), the equilibrative nucleoside transporter and proteins
facilitating endocannabinoid inactivation. Here we have tested these two cannabinoids on
the activity of the descending pathway of antinociception.

EXPERIMENTAL APPROACH

Electrical activity of ON and OFF neurons of the rostral ventromedial medulla in
anaesthetized rats was recorded extracellularly and tail flick latencies to thermal
stimuli were measured. CBD or CBC along with various antagonists were injected into the
ventrolateral periaqueductal grey.

KEY RESULTS

Cannabidiol and CBC dose-dependently reduced the ongoing activity of ON and OFF neurons
in anaesthetized rats, whilst inducing antinociceptive responses in the tail flick-test.
These effects were maximal with 3 nmol CBD and 6 nmol CBC, and were antagonized by
selective antagonists of cannabinoid CB(1) adenosine A(1) and TRPA1, but not of TRPV1,
receptors. Both CBC and CBD also significantly elevated endocannabinoid levels in the
ventrolateral periaqueductal grey. A specific agonist at TRPA1 channels and a synthetic
inhibitor of endocannabinoid cellular reuptake exerted effects similar to those of CBC
and CBD.

CONCLUSIONS AND IMPLICATIONS

CBD and CBC stimulated descending pathways of antinociception and caused analgesia by
interacting with several target proteins involved in nociceptive control. These compounds
might represent useful therapeutic agents with multiple mechanisms of action.